The Advanced Practitioner's Role in Managing Bone Health in Patients With Cancer

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

In this next segment, we are going to talk more about duration, and we're going to talk about those AEs that we didn't yet address in the prostate case, but we're going to move into a breast cancer case as context for this discussion. In this segment, we will be diving further into some of the AEs, or adverse events, associated with the use of bone-modifying agents. Christine will introduce our next patient, a woman with breast cancer. Go ahead, Christine.

Christine Cambareri, PharmD, BCPS, BCOP, CSP:

Thanks, Carrie. So building upon what we've already talked about today, I'm going to introduce patient M.S. She is a 58-year-old female who was originally diagnosed at age 55 in 2016 with post-menopausal stage 2B invasive ductal breast cancer. Her disease was node positive, estrogen and progesterone receptor positive, and HER2 negative. Her comorbidities include type 2 diabetes, managed with metformin only, as well as hypertension, for which she's on hydrochlorothiazide and lisinopril. In the fall of 2016, she was treated with Taxotere and Cytoxan for four cycles followed by daily letrozole for her hormone positive breast cancer. At the time of initiation of adjuvant hormonal therapy, in January of 2017, she had a DEXA scan which showed normal to mildly osteopenic bone mineral density. Subsequently in January of 2019, she presented for routine follow-up to her medical oncologist reporting mild pain in her central chest, her breastbone area, that she began noticing prior to the Thanksgiving holiday weekend after she had been moving around furniture in preparation for hosting guests at her home.

The pain was mild and intermittent, but progressed and became constant. Imaging was done based on the symptoms she was submitting to the medical oncologist and chest x-ray and plain films of the sternum showed a lytic lesion occupying more than half of the surface area of the sternum with moderate bony destruction. A follow-up bone scan that was prompted because of the chest x-ray plain film showed diffuse uptake in the sternum, but fails to reveal any other site of bone metastasis. CT scans of the chest, abdomen, and DEXA scan show a 4% decline in bone mineral density of the L spine over the last 2 years.

Her T-score is now -1.9, and in the right hip, her T-score is -1.3, with the associated decline of 3%. looking at her labs in conjunction with what her imaging had shown, we saw normal CBC with differential and platelets, normal liver function tests, except for elevated alk phos of 172. Her serum creatinine is 1.5 milligrams per deciliter, which correlates to a creatinine clearance of 51. Her calcium and electrolytes are within normal limits. At this point, based on these updated imaging and patient symptoms, her medical oncologist starts her on fulvestrant, 500 milligrams intramuscularly, a systemic therapy for her metastatic disease with a loading dose every 2 weeks for 1 month, and then continued monthly dosing. And I'll hand the case back over to Carrie now.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Thanks, Christine. So this is a kind of case I've seen many times in my practice as an oncology nurse practitioner. This is a postmenopausal woman who a couple years after early diagnosis or diagnosis rather than early stage breast cancer has now recurred with her hormone-sensitive breast cancer. She already comes into that recurrence with some bone loss from aging and from her own treatment with an aromatase inhibitor, which robs the bone of estrogen. She also has some critical comorbidity context to consider when initiating treatment for bone loss prevention or prevention of skeletal-related events. You know, what is that? Well, she is on some hypertensive meds. She has a long history of hypertension and she has some renal insufficiency and she has bony destruction. So she does, although she only has limited bony disease in the sternum alone, she has bony destruction there.

So we've got to see her serum creatinine already of 1.5, as you said, and she's going on another agent Faslodex or fulvestrant. That is going to further rob her bones of the estrogen needed to maintain mass. So I'd certainly be doing another DEXA scan in this case to see where she is. I'd certainly be making sure she's still on her calcium and vitamin D. We've talked extensively about those issues so I'm not going to go into them more here. I would monitor her DEXA, probably yearly.

I'd be looking at x-rays and bone scans or PET scans every three months while on treatment. We've already talked about what that treatment would be. And in my case, she's got lytic disease. I mean, neither ESMO nor ASCO guidelines would refute that she needs to start at this point, even though it's only in a solitary location. I'm curious if your colleagues at Penn, whom I know you spoke with about this case, had a different take on it. You know, would they consider radiotherapy here in addition to bone modifying agents? What were the discussions you had about dosing and schedule with them? Where or how are you factoring in the fact that she has renal insufficiency in making decisions about therapy? Tell me a little bit more about what they had to say.

Christine Cambareri, PharmD, BCPS, BCOP, CSP:

Sure. And so to comment on other management of where this disease was with the single site, a few of the providers that I spoke with said that they would consider radiation oncology, certainly a consult to get an opinion on if it's something that would be worth doing and allowing the patient to be involved in that decision making. But almost everybody said that they would be starting a bone modifying agent. And when I probed on, so which one would you use? there was heavy discussion around there's not necessarily a preference, but where people feel like their hands are tied or they're driven one way or another to choose zoledronic acid over denosumab sometimes unfortunately is insurance driven. But in this situation, when we were talking about where the patient's creatinine clearance fell, she was on the cusp of what I recommend the limits are.

We want to be above 60 mils per minute for creatinine clearance for using zoledronic acid. And so a lot of the providers that I spoke with and myself included would feel like we would recommend starting Xgeva, 120 milligrams monthly for a period of 2 years for this patient. I think another thing that is important before initiating any kind of bone modifying agent therapy, which will come into play when we talk a little bit more about the AEs later on for osteonecrosis of the jaw prevention is assessing what this patient's dental status is as well. And seeing if she seen a dentist or has a history of significant dental co-morbidities that either need to be handled preemptively or where we're at to make sure that we can, again, have that level-setting conversation for side effects that can occur with initiating these kinds of therapies, especially for a 2-year period, which is what we are potentially starting her up to do.

I think the role for radiation therapy also came into play with this oligometastatic site is painful to the patient. And so how offering something like radiotherapy could help the patient's pain over time and support with using things like nonsteroidal anti-inflammatories and steroids, if that's appropriate based on her risk factors, which it looks like. I don't know if I would necessarily push a lot of the NSAID use like she said, she was already doing just because of where her serum creatinine is. And because her kidneys are already taxed with her history of chronic hypertension and being on those medicines. So it's definitely a balance of how to offer her symptomatic relief while preserving target end organ function, while getting some of these other therapies on board for her.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Such a great case. It really allows us to discuss so many contextual factors here. And while Dr. Sieber, you and Saneese particularly at the moment specialize in GU malignancies, I think there are many aspects of this case that you could comment on in terms of at this time point of initiating therapy. And in this case, the choice seems to lead more towards denosumab because of her renal insufficiency. What else would you add? Like what else do we need to be thinking about even with denosumab and renal insufficiency in terms of supportive care management? Saneese, do you want to take that one on?

Saneese Stephen, MPAS, PA-C:

Sure. I know there's not great recommendations on which DTA to start. So I'll comment on that first a little bit. There's been several trials that in multiple myeloma, also on breast cancer and prostate cancer, where they compared head to head denosumab versus zoledronic acid. And denosumab seems to have a superior efficacy in terms of preventing the first skeletal related event. And they actually combined all three cases and a meta-analysis several years ago, and also found the benefit overall was with denosumab. But regardless there's not a recommendation to start a specific bone target agent. That decision really weighs on multiple factors, including potential side effects and renal function. Zoledronic acid has acute phase symptoms with myalgias and fever that you don't see as much with denosumab. The renal function is certainly a big issue and we have to renal dose the zometa based on the creatinine clearance, which you don't so much with denosumab.

We still check renal function with denosumab, even though it's not metabolized by the kidney. There's a higher risk of hypercalcemia and hyperphosphatemia once the renal function is diminished, even with denosumab. So that kind of gets into the caveat of how to dose and when to monitor and would monitor and treat hypocalcemia and hypophosphatemia prior to giving monthly or regular denosumab injections. The other point is duration. I think duration, and I think in this breast cancer patient, you mentioned 2 years of denosumab, you know, the trials that looked at duration with previous bone targeted agents with Zometa was very different terms of, as you know Zometa, zoledronic acid, is actually incorporated into the bone matrix, and it can have long standing work even after you stop it in 2 years. It's a very different mechanism, as you know, for denosumab, which is a monoclonal antibody.

And there's the limitation on duration is not as clear with denosumab. And as Christine mentioned, there's also the potential of side effects once you discontinue denosumab. So in a way you're almost married to the drug when you start it. You're kind of giving it indefinitely, I think in many cases, because of the rebound osteolysis and potentially vertebral fracture risk. You're giving it pretty much lifelong. I don't necessarily think we would be giving it in the hospice setting. I think because of the cost factor, even though that's more recommended, considering the hospice setting, I don't see how that's logistically possible because of cost issues and continuing therapy of that nature and hospice would not be reasonable. But I'll stop there. And you know, maybe Dr. Sieber can pick up on the other comments.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Yeah. Particularly duration, we're going to take our case into hypocalcemia and ONJ, so if you could briefly comment Dr. Sieber on duration issues?

Paul Sieber, MD:

Well, I think without a doubt duration is a problem. And then that's why I think in my space, in the castrate resistant prostate cancer space, that's why, and Saneese said the same thing earlier, we try to be a little cautious up front, but you have to still deal with osteoporosis. So that's the dilemma. And in this case we're going to make this abrupt change here at 2 years. Well, what if the lady's osteoporotic now? So you can tell an osteoporotic, we're not going to treat you? We're just going to take our chances because the agents, whether it's zoledronic acid or denosumab, stabilize bone loss. There's a modest improvement of bone density. But if you have a significant osteoporotic, they're not going to suddenly be normal. They're going to be a little less osteoporotic at least by their T-score. So I think you're still having, again, a lot of breast cancer patients running around for a lot of years, they still have bone health issues. So it kind of complicates things a bit. I think you have to pay extra attention to her oral care. You have to pay extra attention to maybe we're going to have to at some point stop, but I don't think you can get away with ignoring what we do with our long-term bone health.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Such good points. So hypocalcemia, one thing just to be super clear about in the use of denosumab is that while it can be used at the same dose, even in renal insufficiency, the issue is that it does increase the risk for hypocalcemia in that scenario. We are going to be extra cautious about ensuring that the patient is taking calcium supplementation on top of whatever dietary amount she's getting. And we're going to be monitoring calcium regularly. You know, we had carried this case further through to talk about her presenting to clinic with symptoms of hypocalcemia. And I'm going to abbreviate that here and say she had come in feeling a little dizzy with some tingling in her extremities. She had a cold in her household and essentially what we find out is that due to her symptoms, she had stopped her calcium vitamin D because she was taking so many other things for her cold.

And so her calcium showed that she was hypocalcemic with a normal albumin. She had a calcium level of 6.3 and it had been 9. So also she had worsened from a creatine clearance of 51 to around 30 due to her recent viral and illness causing dehydration. So that's sort of the perfect storm of where hypocalcemia could manifest. And in her case then we held her Xgeva that day, encouraged her to resume her calcium and vitamin D along with oral hydration at home, and gave her infusion of fluids in clinic. So, Christine, do you want to round that out, that case in terms of just following up to make sure she gets back to where she needs to be, etc.?

Christine Cambareri, PharmD, BCPS, BCOP, CSP:

Sure. And so like Carrie mentioned, this is the perfect storm and situations I've definitely been involved with where it's easy for some of the other therapies to fall off. I think offering immediate supportive care to kind of quote unquote tank the patient back up with hydration, if appropriate and then a decision that can be had in the collaborative care team offering a calcium gluconate infusion while there, if appropriate again, considering your patients specifically something that is definitely reasonable. I think making sure the patient is trending back with her calcium is the next important kind of follow-up point. And so a plan lab check, I think a week after seeing the patient in clinic makes the most sense. And in this case specifically, we design that a week later, the calcium was up to 7, which is better than where we were at. So we're seeing the benefit of hydration, our calcium gluconate, and the oral repletion being incorporated again, and her renal function is slowly getting better, so not back to where it was, we're at 43 mils per minute, so not back to her 51, but again, better than where we were. The discussion can be had, you know, I think at this point it doesn't make sense to bring her back in for Xgeva right now, or for her denosumab. Let's wait until her next visit when she's in for her next monthly fulvestrant dose. So 3 weeks later, her calcium is again to 8 and her renal function is back to its baseline, the patient is hydrating at home, adequate calcium vitamin D on board. Everyone's over this cold that made its way through her home. And so now I think the position where we're at as providers and what we should do next for this patient is, should we give the next dose of Xgeva or denosumab? Honestly, you can go either way.

So I think you could argue let's hold it maybe 1 more month and see if it gets better, but then you can also make the point that because of the disease she has, it doesn't make sense to hold, but we're doing risk versus benefit for what's the right time interval. And so, again, like we talked about, or like Dr. Sieber said in our ivory towers or on paper, it makes sense, yes, 4 weeks, no matter what let's keep going, but real life happens. And sometimes we do need to extend the intervals based on our patient specifically, and not necessarily that cookie cutter approach. And so what I've seen done often in this kind of we're managing to our patient and doing the dance, so to speak, with our patients specifically. And in this case, she might be someone that we could say needs to be on every-6-week dosing to maintain those adequate calcium levels so she doesn't bottom out and it's more so driven by maybe her more compromised renal function that she has based on her chronic hypertension and things that she has going on.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Saneese?

Saneese Stephen, MPAS, PA-C:

I think ONJ of course is very real. I've seen several patients in the past 2 years who have had ONJ so, you know, assessing the patient is very important and getting the right consults in quickly and interrupting the dosing is important. The guidelines are very not concrete on duration of interruption. You have to look at 2 weeks up to 3 months of interruption in some cases, but I think it depends on the healing of the patient's gum and the context with the discussion with the dentist that'll drive that decision-making. But I think the interval dosing data is out for the REACT group publishing some data, and also as a data from reduced trial that's coming out at the end of next year that's going to talk about interval dosing in prostate cancer, as well as breast and myeloma. So I think we're anxious to see if interval dosing three or less frequent dosing can be useful without putting further risk for the patient.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Thanks for bringing us back to supporting data and ongoing trials and advancing the discussion of this case to ONJ. So where we left off with the portion of the hypocalcemia case, let's consider that she did go on a modified dosing schedule and was on every-6-week dosing to maintain adequate calcium levels. Perhaps she just didn't rebound. And now it's 16 months into her XGEVA. This is the scenario where ONJ could become an issue over time as you saw from those earlier data. After 2 years, she's not quite there yet, but we certainly know it's over time, that risk of ONJ or osteonecrosis of the jaw becomes an issue. Let's say in this woman's case, she not seen a dentist in over a year due to the COVID pandemic. It's real. Right? She's having some teeth issues, and dental evaluation does recommend she receives a few extractions and new implants.

These are real dental procedures that increase the risk of osteonecrosis of the jaw. So she's talking to us about whether or not she can schedule those dental procedures. Her disease remain stable on faslodex. she's on every-6-week denosumab. So in my practice extraction is a risk for sure, but so is an abscess. So we need to allow her to have this extraction if it's dentally indicated. We want to try and avoid implants though for sure during bone-modifying therapy. Increased risk of skeletal-related events is going to be a risk we're taking during a drug holiday, but she clearly needs a drug holiday if she's getting a full extraction, in my opinion. We want to bring in the multi-professional team on decision-making so that we can make a case by case basis for her here. So I'm going to throw it back to you all. Should we be holding her Xgeva, like I strongly would recommend in my particular practice? How long? What else are you considering during this drug holiday so that she can get her extractions? Let me start with you, Christine.

Christine Cambareri, PharmD, BCPS, BCOP, CSP:

Thank you, Carrie. Yeah, I would agree withholding, with your sentiments, especially since the patient is having active issues. I would say if you can compromise or make a plan with the dentist, like Saneese had mentioned, I think having open lines of communication and making sure that the patient goals are ongoing. Again, we're looking at patients with advanced disease that are living much longer. Bone health is very important as is mouth health and dental health and the risk associated with each of those procedures, extractions carry less of a risk, although they do carry a risk for osteonecrosis of the jaw.

Implants are definitely, because of where the dentist is manipulating the bone more, so that we are more worried about that patient having an increased risk of ONJ. And so kind of discussing again in now that we're looking at our patient in this specific situation, does it make sense to do extractions right now with a shorter drug holiday of a period of a week before the planned extract? Make sure she's been off of the therapy for a little bit and after the extraction waiting at least a month or a month and a half before considering resumption of her denosumab.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

So Dr. Sieber, what would you concretely do? How would you hold? For how long? What would you consider when reinitiating?

Paul Sieber, MD:

I'm going to defer to my oral surgeon. I mean, I think they have a sense that this is a bad actor, so I want them to tell me their thoughts before I make my decision. I'm willing to look in their mouth and say, Oh, their jaw, the gum looks okay. But if they feel like they may look okay into the surface, below the surface, I think there's really trouble brewing. This guy's got a rotten mandible. I think there are certain cases. They just say, this person needs to be off drugs indefinitely. So I really rely on their insights along with just looking in their mouth, which is something I've gotten used to after the years of playing around with this stuff to say, Hey, they're healed. They're not healed. But again, I think it's collaborative with the oral surgeon. That's absolutely critical.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Saneese?

Saneese Stephen, MPAS, PA-C:

I agree with both Christine and Dr. Sieber. A dental oncologist who's familiar with bone targeted agents and the impact on gum and dental issues is probably the best person to address this with.

Carrie Tompkins Stricker, PhD, RN, ANP-BC:

Sometimes folks aren't as lucky as we are to have access to those specialists though so I want to make sure that we meet the needs of our broader audience. What I would say in that regard is have a conversation. Get on the phone with the dentist, even if it isn't a credentialed oral and maxillofacial surgeon. You know? Talk to the dentist in your community and make these decisions together. So interdisciplinary collaborative care is super crucial here. We do have data to help support us in decision making. We'll share some of those references with you, but they include things like the International ONJ Task Force that recommends that treatment should be withheld after invasive dental surgery in patients receiving denosumab or IV or high-dose bisphosphonates, although there's limited data to support that decision. In Italy, they suggest that bisphosphonates and denosumab should be held for at least for a week prior and for 6 weeks following, but note that that's purely based on expert opinion.

So we really do need to have collaborative discussions. To prevent all of this we want to talk to our patients about maintaining excellent oral hygiene whenever possible and the risk of MRONJ, so osteonecrosis of the jaw, is low, but not non-existent. It's approximately 1% in patients exposed to zoledronic acid. It is still though 50 to 100 times higher than in placebo, and again, the overall incidents in denosumab for cancer patients was just north of 1% as well, about 1.7%. So it’s a real risk to consider.